There has been a dramatic rise in the number of severe fungal infections due to a constant rise in the number of individuals who are immunocompromised. Strong similarities in the basic eukaryotic metabolic pathways between fungi and mammalian cells have hindered the development of antifungal agents because many compounds that are effective at inhibiting fungal growth are also toxic to host cells. It is becoming clear that novel antifungal agents alone are unlikely to significantly reduce the mortality rate of fungal infections without the aid of new therapeutic approaches. One promising approach is to combine current antifungal treatments with agents that enhance the host immune system's ability to eliminate the microbe. Such an approach requires a detailed understanding of the complex interaction between host and pathogen. Infections due to Candida, Aspergillus, and Mucorales are the most common fungal infections that are associated with poor outcome. Together, these three phylogenetically and biologically distinct fungi are responsible for approximately 90% of the invasive fungal infections that occurred in North America between 2004 and 2008. Here we will combine dual-species RNA-seq, comparative genome analysis, well established animal models and fungal genetics to systematically and comprehensively analyze the host-pathogen interactions of these diverse fungal pathogens. Analyzing all three different types of fungi using the same approach will enable us to define commonalities as well as key differences among the organisms and the responses they elicit in the host. The proposed studies will provide a wealth of information regarding gene function and regulation in both the fungus and the host and will likely lead to the identification of novel therapeutic targets to treat this increasingly serious cause of human disease.